Individual patient data meta-analysis of dynamic cerebral autoregulation and functional outcome after ischemic stroke

Graphical abstract

We assessed the quality of included data based on the primary research papers from which the data were derived by comparing the study methods against the recently updated CARNet White Paper criteria 10 .The CARNet White Paper outlines best practice for the conduct of TCD-based cerebral autoregulation research, and covers domains such as data acquisition and preprocessing, transfer function methodology and reporting, alternative metrics, and normative data and thresholds 10 .Quality of study reporting for observational studies was assessed using the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines 13 .Quality assessment using the STROBE criteria was conducted independently by two reviewers (LB & EH), and the assessment against the CARNet white paper criteria was conducted independently by pairs of reviewers (LB & JM, SP & DS, AS & RN, PC & MM, AR & PB).Disagreements were resolved by discussion between reviewers.Quality assessments were based on the original, published reports and were conducted independently of the IPDMA.A statistical assessment of publication bias using funnel plots was not possible due to insufficient aggregate data provided in the original published reports.Much of the outcome data obtained for this IPDMA was unpublished as well as published and therefore reduces the risk of publication bias in this analysis.

11, SM1
Identifying studies -search 8 Present the full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

SM5
Study selection processes 9 State the process for determining which studies were eligible for inclusion.

11, SM1
Data collection processes 10 Describe how IPD were requested, collected and managed, including any processes for querying and confirming data with investigators.If IPD were not sought from any eligible study, the reason for this should be stated (for each such study).

SM1, 11
If applicable, describe how any studies for which IPD were not available were dealt with.This should include whether, how and what aggregate data were sought or extracted from study reports and publications (such as extracting data independently in duplicate) and any processes for obtaining and confirming these data with investigators.

Data items 11
Describe how the information and variables to be collected were chosen.List and define all study level and participant level data that were sought, including baseline and follow-up information.If applicable, describe methods of standardising or translating variables within the IPD datasets to ensure common scales or measurements across studies.

11,12, SM6 IPD integrity A1
Describe what aspects of IPD were subject to data checking (such as sequence generation, data consistency and completeness, baseline imbalance) and how this was done.

11
Risk of bias assessment in individual studies.
12 Describe methods used to assess risk of bias in the individual studies and whether this was applied separately for each outcome.If applicable, describe how findings of IPD checking were used to inform the assessment.Report if and how risk of bias assessment was used in any data synthesis.

SM3
Specification of outcomes and effect measures 13 State all treatment comparisons of interests.State all outcomes addressed and define them in detail.State whether they were pre-specified for the review and, if applicable, whether they were primary/main or secondary/additional outcomes.Give the principal measures of effect (such as risk ratio, hazard ratio, difference in means) used for each outcome.

12, 13
Synthesis methods 14 Describe the meta-analysis methods used to synthesise IPD.Specify any statistical methods and models used.Issues should include (but are not restricted to): • Use of a one-stage or two-stage approach.
• How effect estimates were generated separately within each study and combined across studies (where applicable).
• Specification of one-stage models (where applicable) including how clustering of patients within studies was accounted for.
12, 13 • Use of fixed or random effects models and any other model assumptions, such as proportional hazards.
• Methods for quantifying statistical heterogeneity (such as I 2 and  2 ).
• How studies providing IPD and not providing IPD were analysed together (where applicable).
• How missing data within the IPD were dealt with (where applicable).

A2
If applicable, describe any methods used to explore variation in effects by study or participant level characteristics (such as estimation of interactions between effect and covariates).State all participant-level characteristics that were analysed as potential effect modifiers, and whether these were pre-specified.

12, 13
Risk of bias across studies 15 Specify any assessment of risk of bias relating to the accumulated body of evidence, including any pertaining to not obtaining IPD for particular studies, outcomes or other variables.

11, 12, SM3
Additional analyses 16 Describe methods of any additional analyses, including sensitivity analyses.State which of these were pre-specified.

Study selection and IPD obtained 17
Give numbers of studies screened, assessed for eligibility, and included in the systematic review with reasons for exclusions at each stage.Indicate the number of studies and participants for which IPD were sought and for which IPD were obtained.For those studies where IPD were not available, give the numbers of studies and participants for which aggregate data were available.Report reasons for non-availability of IPD.Include a flow diagram.

SM5 Study characteristics 18
For each study, present information on key study and participant characteristics (such as description of interventions, numbers of participants, demographic data, unavailability of outcomes, funding source, and if applicable duration of follow-up).Provide (main) citations for each study.Where applicable, also report similar study characteristics for any studies not providing IPD.

13-15
IPD integrity A3 Report any important issues identified in checking IPD or state that there were none.

11
Risk of bias within studies 19 Present data on risk of bias assessments.If applicable, describe whether data checking led to the up-weighting or downweighting of these assessments.Consider how any potential bias impacts on the robustness of meta-analysis conclusions. 16 Results of individual studies 20 For each comparison and for each main outcome (benefit or harm), for each individual study report the number of eligible participants for which data were obtained and show simple summary data for each intervention group (including, where applicable, the number of events), effect estimates and confidence intervals.These may be tabulated or included on a forest plot.

SM7
Results of syntheses 21 Present summary effects for each meta-analysis undertaken, including confidence intervals and measures of statistical heterogeneity.State whether the analysis was pre-specified, and report the numbers of studies and participants and, where applicable, the number of events on which it is based.

16-25 16
When exploring variation in effects due to patient or study characteristics, present summary interaction estimates for each characteristic examined, including confidence intervals and measures of statistical heterogeneity.State whether the analysis was pre-specified.State whether any interaction is consistent across trials.
Provide a description of the direction and size of effect in terms meaningful to those who would put findings into practice.

Risk of bias across studies 22
Present results of any assessment of risk of bias relating to the accumulated body of evidence, including any pertaining to the availability and representativeness of available studies, outcomes or other variables.

SM18
Additional analyses

23
Give results of any additional analyses (e.g.sensitivity analyses).If applicable, this should also include any analyses that incorporate aggregate data for studies that do not have IPD.If applicable, summarise the main meta-analysis results following the inclusion or exclusion of studies for which IPD were not available.

Summary of evidence 24
Summarise the main findings, including the strength of evidence for each main outcome.

Strengths and limitations 25
Discuss any important strengths and limitations of the evidence including the benefits of access to IPD and any limitations arising from IPD that were not available.

26, 27
Conclusions 26 Provide a general interpretation of the findings in the context of other evidence.

26, 27
Implications A4 Consider relevance to key groups (such as policy makers, service providers and service users).Consider implications for future research.

27, 28
Funding Funding 27 Describe sources of funding and other support (such as supply of IPD), and the role in the systematic review of those providing such support.

4
A1 -A3 denote new items that are additional to standard PRISMA items.A4 has been created as a result of re-arranging content of the standard PRISMA statement to suit the way that systematic review IPD meta-analyses are reported.
© Reproduced with permission of the PRISMA IPD Group, which encourages sharing and reuse for non-commercial purpose

Table S2. STROBE Checklist
Checklist of items that should be included in reports of observational studies 13 .

Item
4. Figure S1.PRISMA flow diagram for selection of studies/participating centres included in this review Indicate the study's design with a commonly used term in the title or the abstract (b) Provide in the abstract an informative and balanced summary of what was done and what was found Cohort study-Give the eligibility criteria, and the sources and methods of selection of participants.Describe methods of follow-up Case-control study-Give the eligibility criteria, and the sources and methods of case ascertainment and control selection.Give the rationale for the choice of cases and controls Cross-sectional study-Give the eligibility criteria, and the sources and methods of selection of participants (b)

Figure S2 .
Figure S2.Ordinal mRS results within 24 hours or individual level i.e. whether eligible participants were included (and ineligible participants excluded) from a study that included a wider population than specified by the review inclusion criteria.The rationale for criteria should be stated.Describe all methods of identifying published and unpublished studies including, as applicable: which bibliographic databases were searched with dates of coverage; details of any hand searching including of conference proceedings; use of study registers and agency or company databases; contact with the original research team and experts in the field; open adverts and surveys.Give the date of last search or elicitation.
Data dictionary summarising the data points collected (where available) for this IPDMA, the definitions for each variable, data type, and codes assigned.*dCAparameters for the affected and unaffected hemisphere categorised by time point of measurement from event (within 24 hours, 24-72 hours, 4-7 days, and more than 3 months).ARI= autoregulatory index, CBv= cerebral blood velocity, ECASS= European Cooperative Acute Stroke Study, ECG= electrocardiogram, LACS= lacunar stroke, LF= low frequency, LVO= large vessel occlusion, MCA= middle cerebral artery, mRS= modified Rankin Scale, Mx= mean flow index, NIHSS= National Institutes of Health Stroke Scale, NIRS= near-infrared spectroscopy, PACS= partial anterior circulation stroke, PCA= posterior cerebral artery, POCS= posterior circulation stroke, Prx= pressure reactivity index, TACS= total anterior circulation stroke, VLF= very low frequency.study

Table S4 . Demographics of total sample and across each time point.
Cohort study-For matched studies, give matching criteria and number of exposed and unexposed

Table S6 .
Univariable analyses for dCA parameters from the affected hemisphere for each time point, with modified Rankin Scale (mRS) as an ordinal variable.Analyses were conducted with cumulative link mixed models with the center of origin included as a random effect.ARI=autoregulation index, CBV=cerebral blood velocity, h=hours, LF=low frequency, mo=months, mRS=modified Rankin Scale (mRS), OR=odds ratio, SE=standard error, VLF=very low frequency.Phase measured in radians.Analyses on ordinal mRS at 4-7 days and 3 months were not conducted due to insufficient sample size.Measures with means < 1 were rescaled to represent changes per 1 SD.

Table S7 . Univariable analyses for dCA parameters from unaffected hemisphere for each time point with raw p values reported
OR=odds ratio, SE=standard error.Analyses were conducted with generalized linear mixed models.